Women live longer than men, and different age-related diseases afflict women and men at different rates. Our poor understanding of the basis of these sex-differences promote disparities between men and women in the success of treatments of age-related diseases. The Insulin and Insulin-like Signaling (IIS) molecular pathway is known to regulate longevity. The overall goal of the proposed research program is to test if hormones that regulate the IIS pathway contribute to sexual dimorphism in longevity and aging. Research on one of these hormones, IGF2, has been limited by the lack of an animal model that naturally expresses IGF2 in adulthood. To overcome this barrier, this research will use a novel model system, the brown anole lizard, which naturally expresses IGF2 through adulthood similarly to humans, to address questions on the role of IGF2 in aging. This proposal has two Specific Aims that include experiments both in a brown anole laboratory colony and in a lizard cell culture system. Specific Aim 1 uses a longitudinal experiment at the organismal level to define the respective roles of IGF1 and IGF2 in sexual dimorphism of aging and longevity. Specific Aim 2 uses cell culture experiments to test whether the male cellular environment is pro-aging, and if sex differences in IIS signaling become programmed with age. This contribution will be significant because it will remove a blind spot in our knowledge on the function of the somatotropic axis on the sex-specific biology of aging by developing and using an alternative terrestrial vertebrate model and comparative approaches that are synergistic with established models. Furthermore, the integration of research and undergraduate education with this project is designed to provide extensive hands-on research experience related to the biology of aging for 50+ undergraduate researchers annually. The proposed research and developed methodology will open new avenues of research, currently unattainable with our standard model systems, on IGF2 and other top regulators of the IIS pathway that play a role in the natural processes of aging.